(r)-1-(2-furoyloxy)-3-methylbutyl-pencillin compounds

ABSTRACT

Compounds represented by the following formula   WHEREIN A is a substituted or unsubstituted heterocyclic radical and T is a C2-C5 alkyl, alkenyl, cycloproplymethyl, cyclobutylmethyl or cyclopentyl group A PROCESS FOR THEIR PREPARATION AND NOVEL INTERMEDIATES THEREFOR ARE DISCLOSED. These compounds are useful antibiotics.

United States Patent 11 1 Furlenmeier et al.

[451 Oct. 1,1974

[ (R)- l-( Z-FUROYLOXY )-3-METHYLBUTYL- PENCILLIN COMPOUNDS [76]Inventors: Andre Furlenmeier, 119

Wettsteinallee, Basel; Peter Quitt, 40 Mittlerer Rainweg, Fullinsdorf;Karl Vogler, 69 Wenkenstrasse, Riehen; Paul Lanz, l6 Freidorfweg,Muttenz, all of Switzerland 22 Filed: Jan. 3, 1972 21 Appl. No.: 215,187

[30] Foreign Application Priority Data OTHER PUBLICATIONS Neal et al.,Chemical Abstract 70: 4105F (1969).

Petersone et al. Chemical Abstract 73: 86326c.

Primary ExaminerNicholas S. Rizzo Assistant Examiner-Ralph D. McCloudAttorney, Agent, or FirmSamuel L. Welt; Jon S. Saxe; R. Hain Swope [5 7]ABSTRACT Compounds represented by the following formula wherein A is asubstituted or unsubstituted heterocyclic radical and T is a C C alkyl,alkenyl, cycloproplymethyl, cyclobutylmethyl or cyclopentyl group aprocess for their preparation and novel intermediates therefor aredisclosed. These compounds are useful antibiotics.

2 Claims, N0 Drawings 1 (R)-l-(Z-EUROYLOXYl-3-METHYLBUTYL PENICILLINCOMPOUNDS DETAILED DESCRIPTION OF THE INVENTION The present invention isdirected to novel 6- acylaminopenicillanic acid compounds represented bythe general formula halogen represents all the halogens with fluorine,bromine and chlorine being preferred. Alkyls or alkenyls represented byT in formulas I and Il may be straightor branched-chain. Examples ofsuch substituents include ethyl, n-propyl, isobutyl, n-pentyl, 3-methylbutyl, neopentyl, vinyl, allyl, methallyl, butenyl and pentenyl.The C to C alkyl, alkoxy, alkoxycarbonyl and alkanoylamino groupsreferred to herein are those wherein the alkyl moiety contains from oneto three carbon atoms.

Preferred 6 -aminopenicillanic acid compounds in accordance with theinvention are those wherein A in the above formulas is 3-pyridyl,2-methyl-4-pyridyl, 3- isoxazolyl, 4-oxazolyl, 2-oxo-2-pyrrolidinyl,pyrazinyl, tetrahydro-Z-furyl, 2-acetamido-4-thiazolyl, 1,5dimethyl-Ii-pyrazolyl, tetrahydro-4-pyranyl, 1,2,3- thiadiazol-4-yl,2-furyl or 4-pyridyl. The preferred compounds according to the inventionare those wherein T is an alkyl or alkenyl group containing four or fivecarbon atoms. An especially preferred group of compounds in accordancewith the invention are set forth in Table below. Preferred among thisgroup is the compound represented by formula I wherein A is 2- furyl andT is 2-methylpropyl, i.e., [l-(2-furoyloxy)-3- methylbutyl)l-penicillin,especially the R-form thereof. In the Table, the antimicrobial activityof the compounds tested is expressed in terms of the minimal inhibitoryconcentration in pg/ml. The minimal inhibitory concentration wasdetermined by doubledilution 3Q series in nutrient bouillon. T'l'ieactivity of'the'eam.

pounds is further demonstrated in vivo by establishing an oral CD in themouse against S. aureous and E. coli.

In accordance with the present invention, the corripounds represented byformula I are prepared by con- 1 35 densing 6-amino-penicillanic acid,the carboxyl group Minimum Inhibitory Concentration I mg/ml] CDQJper TheMouse [mg/kg] penicillin sodium Compound S. aureous FDA E. coli 1346 S.aureous (Schoch) E. coli 1346[(R)-l-(2-furoyloxy-3-methyl-butyl1penicillin sodium 0.073 73 0.7 16

[(R)-l-(isonicotinoyloxy)-3-methyl-butyllpenicillin sodium 0.156 19 1.118

(R)-3-methyl- 1 (S )-pyroglutamoyloxy-butyllpenicillin 0.312 0.625 21037 sodium [(R)-3 -methyl- 1 l,2,3-thiadiazol-4-ylcarbonyl )oxyl- 0.3 I 210 7.2 93

[(R)-3-methyl-l-{[tetral'Wropyran-Z-ybcarbonylloiyy 1.25 19 3.1 27

butyllpenicillin sodium[(R)-l-{[(1,5-dimethylpyrazol-3-yl)-carbonyl]oxy}-3- 0.625 78 2.9 42

methylbutyllpenicillin sodium [(R)-l-{[(2-acetamido-4-thiazolyl)-carbonylloxy}-3- 1.25 10.0 2.4 47

methylbutyllpenicillin sodium [(R)-3-methyl-l-[(RS)-tetrahydro-2-furoyloxy]butyl]- 1.25 10.0 1.6

wherein A aafifiaveirie meaning g iveii abovefan d their functionalderivatives.

-ofiivhich' "rs m a protected form, with the 'riovl compoundsrepresented by formula II or a functional deriv- In accordance with thepresent invention, the term ative thereof. Such functional derivativesare conventional and include, for example, halides, azides, anhydridesparticularly mixed anhydrides with strong acids reactive esters such asthe N- hydroxysuccinimide esters, amides, such as imidazolides and thelike. After the reaction is completed, the protecting group is cleavedoff and, if desired, the product is converted into a salt.

Examples of methods whereby the carboxyl of 6- amino-penicillanic acidcan be protected include conversion into a readily cleavable ester suchas, for example, the benzyl ester, a p-bromophenacyl ester or a silylester such as the trimethyl silyl ester, or by salt formation with aninorganic or tertiary organic base such as,

for example, triethylamine. When the condensation of 6-aminopenicillanicacid and the compound represented by formula II is completed, the esterprotecting group can be easily removed by methods known in the art. Forexample, a benzyl ester can be easily removed by catalytic hydrogenationsuch as, for example, in the presence of a noble metal catalyst such aspalladiumon-carbon, and a silyl ester can be cleaved by treatingtheproduct with water. Where the carboxyl group of 6-aminopenicillanicacid is protected by salt formation, e.g., with triethylamine, theprotecting group can be cleaved by treatment with acids such as, forexample, hydrochloric acid, sulfuric acid, phosphoric acid, citric acidand the like at low temperatures, e.g., O5C.

The condensation of 6-aminopenicillanic acid, having a protectedcarboxyl group and the compound represented by formula II is carried outby methods well known in the art of peptide chemistry. Thus, forexample, the condensation is effected in the presence of a carbodiimidesuch as, for dicyclohexylcarbodiimide or an oxazolium salt such as, forexample, N-ethyl-S- phenyl-isoxazolium-3'-sulfonate, in an inertsolvent. Suitable solvents include, for example, ethyl acetate,acetonitrile, dioxan, chloroform, methylene chloride, benzene,dimethylformamide and the like. In a like manner, a salt of-aminopenicillanic acid such as, for example, a trialkylammonium salt,is condensed with a reactive functional derivative of a compoundrepresented by formula II. The reaction of 6- aminopenicillanic acidhaving a protected carboxyl group and an acid compound represented byformula II, or a reactive functional derivative thereof, canconveniently be carried out at a temperature between about -40C. and C.,preferably at about 0C.

The novel acid starting compounds represented by formula I] may beutilized as racemates or in an optically pure form. It is preferred touse the R- enantiomers in the practice of the invention. Specifically,the R configuration referred to pertains to the asymmetrical carbon atommarked with an asterisk in formula'lla.

Ila

wherein A and T have the meaning given.v The acid compounds representedby formula II may be prepared by converting a compound represented bythe general formula wherein A'and T" have the meaning given earlier andB represents a protected carboxyl group. H into the free acid form bycleaving. the protecting group. The protected carboxyl group representedby B in the above formula may be a readily cleavable ester group suchas, for example, the benzyl or tert. butyl ester groups. The conversionof the protected carboxyl group into the free acid is readily effectedin the case of the benzyl ester, for example, by catalytic hydrogenationin the presence of a noble metal catalyst. Where the protecting group isthe tert. butyl ester, cleavage may be accomplished by treatment withacid such as, for example, a mineral acid-hydrochloric acidortrifluoroacetic acid and the like. The subsequent conversion of the acidcompounds represented by formula II, if desired, into reactivefunctional derivatives thereof such as, for example, halides, azides,anhydrides, esters, amides and the like may be carried out by methodsrecognized in the art as being conventional.

The compounds represented by formula III above may be obtained byconventional means such as, for example, utilizing known means such asdescribed herein to protect the carboxyl group in a compound representedby the general formula OII IV wherein T has the meaning given earlier,and reacting the resulting product with a compound represented by thegeneral formula ACOOI-I wherein A has the meaning given earlier, forexample, in the presence of benzenesulfonyl chloride. I Tire 6 amderivatives of 6-aminopenicillanic acid provided by the presentinvention possess a broad spectrum of activity against gram-positivemicroorganisms such as Staphylococcus aureus, Diplococcus pneumoniae andStreptococcus pyogenes and gram-negative microorganisms such asEscherichia coli, Proteus vulgaris, Proteus mirabilis and Salmonellatyphi murium. Their antibiotic and bactericidal activity allows them tobe utilized therapeutically and as disinfectants. It is preferred inaccordance with the invention to administer the novel penicillincompounds described herein orally in view of their superior stabilityagainst gastric acid. It is contemplated, in the case of adults, thatoral dosage forms each containing 200-600 mg. of active penicillincompound are administered three or four times daily. This dosage regimenmay be adjusted by the clinician as the therapeutic situation requires.The novel penicillin compounds of the inventionmay also be administeredparenterally, rectally or topically in suitable dosage forms and may beadministered in the form of their pharmaceutically acceptable salts orhydrates.

Examples of the pharmaceutically acceptable salts of the penicillincompounds represented by formula I include salts with inorganic basessuch as, for example, the alkali metal salts. e.g.. the sodium orpotassium salt; ammonium salts; alkaline earth metal salts e.g.. thecalcium salt and the like; and salts with organic bases such as aminecompounds, for example, N-ethyl pipcridinc. procaine. dibenzylamine.N.N-dibenzylethylethylenediamine, alkylamines, dialkylamines or thelike. The foregoing salts can also be hydrated. The hydration can beeffected during the manufacturing process or can occur gradually as aconsequence of the hygroscopic properties of an initially anhydroussalt.

The compounds represented by formula l and their salts can exist asoptically pure isomers and as diastereomer mixtures. The preferredcompounds in accordance with the invention are those wherein the acylgroup substituted on the amine group at position 6 of6-aminopenicillanic acid has the R configuration. Specifically, the Rconfiguration referred to pertains to the asymmetrical carbon atommarked with an asterisk in the following formula wherein A and T havethe meanings given above.

For purposes of administration, the novel 6-acyl derivatives of6-aminopenicillanic acid of the present invention can be combined withconventional compatible organic or inorganic pharmaceutical carriermaterials known in the art. Such materials include, for example, water,gelatin, gums, lactose, starches, magnesium stearate, talc, vegetableoils, polyalkylene glycols, petroleum jelly and the like. Suchpharmaceutical preparations may be in unit dosage form and mayadditionally contain other therapeutically valuable substances orconventional pharmaceutical adjuvants such as preservatives, stabilizingagents, wetting agents, emulsifying agents, buffers and the like. Thepharmaceutical preparations can be in conventional solid dosage formssuch as tablets, capsules, dragees and the like, conventional EXAMPLE 1(R l 2-furoyloxy)-3-methylbutyl]penicillin sodium 264.0 g. of(R)-2-hydroxy-isocaproic acid were dissolved in 1.8 litres of absolutedioxan in a three-necked flask fitted with a stirrer, thermometer andreflux condenser with a calcium chloride tube. The solution was treatedsuccessively with 285 ml. of triethylamine and 236 ml. of benzylchloride and heated at an internal temperature of 100 for 20 hours withstirring in an oilbath. After cooling, the resulting triethylaminehydrochloride was filtered off and washed with 500 ml. of ethyl acetate.The filtrate was evaporated under reduced pressure at 50. The residualoil was dissolved in 800 ml. of ethyl acetate and washed twice with 150ml. portions of 3-N hydrochloric acid, twice with 100 ml. portions of 5percent sodium chloride solution, twice with 150 ml. portions of percentpotassium bicarbonate solution and,twice with 100 ml. portions of 5percent sodium chloride solution. After each of these washings, the oilwas rinsed with 200 ml. of ethyl acetate. The ethyl acetate solutionswere dried over magnesium sulphate and evaporated under reduced pressureat 50. The crude product which was thusobtained was distilled at 0.3Torr (1l2l 15). There was obtained benzyl-(R)-2hydroxy-isocaproate; [(2118.0 (c l in methanol); [1923 1.498.

27 Ml. of benzenesulphonyl chloride were added dropwise at 25 withstirring over a period of 20 minutes to a solution of 23.6 g. offuran-Z-carboxylic acid in 100 ml. of pyridine. The mixture was thenstirred for 30 minutes at 25. A total of 44.4 g. of benzyl-(R)-2-hydroxy-isocaproate were then added dropwise with stirring. The solutionwas warmed to 60 for 2 hours.

The pyridine was then distilled off under reduced pressure at 30-50 andthe residue dissolved in 600 ml. of 3-N hydrochloric acid with theaddition of ice and extracted twice with 250 ml. portions of ethylacetate. The ethyl acetate solutions were washed once with.l00 ml. of3-N hydrochloric acid, twice with 100 ml. portions of water, twice with100 ml. portions of 5 percent sodium bicarbonate solution and twice with100 ml. portions of water and dried with magnesium sulphate. The ethylacetate was distilled off under reduced pressure at 40 and the oil driedfor 60 minutes under reduced pressure at 60. There was thus obtainedbenzyl- (R)-2-(2-furoyloxy)-isocaproate; [011 9.0 (C 4.0 in alcohol).

A total of 55.5 g. of benzyl-(R)-2-(2-furoyloxy)- isocaproate werehydrogenated in 400 ml. of alcohol after the addition of 5 g. ofpalladium-on-charcoal (5 percent) until the theoretical amount ofhydrogen had been taken up. The catalyst was filtered off by suction andthe filtrate evaporated under reduced pressure at 40. The oil thusobtained was dissolved in 250 ml. of 8 percent sodium bicarbonatesolution and the resulting solution washed twice with ml. portions ofether. The pH of the bicarbonate solution was adjusted to pH 2 withconcentrated hydrochloric acid and extracted three times with ml.portions of ethyl acetate. The ethyl acetate solutions were washed twicewith 50 ml. portions of water, dried with magnesium sulphate andevaporated under reduced pressure at 45. The residual oil was dried for2 hours at 0.4 Torr and 40to give (R)-2-(2-furoyloxy)-isocaproic acid;[01], 7.0 (c 4.0 in alcohol).

A mixture of 22.6 g. of the R-2-(2-furoyloxy)- isocaproic acid thusobtained, 80 ml. of absolute benzene and 36 ml. of thionyl chloride waswarmed for 2.5 hours, evaporated and dried. There was thus obtained 24.5g. of R-a-(2-furoyloxy)-isocaproic acid chloride. This was dissolved in70 ml. of methylene chloride and the solution added dropwise at 0 withstirring to a solution of 21.6 g. of 6-aminopenicillanic acid in amixture of ml. of methylene chloride and 23 ml. of triethylamine. Thereaction mixture was kept for 20 hours at 0 and then evaporated underreduced pressure at 20. The residue was dissolved in 150 ml. ofice-water and extracted twice with 50 ml. portions of ether. The pH ofthe aqueous phase was adjusted to pH 2 at 0 with 3-N sulphuric acid andextracted three times with 80 ml. portions of ethyl acetate. The ethylacetate solutions were collected and washed three times with 20 ml.portions of ice-cold 5 percent sodium chloride solution, dried withmagnesium sulphate and evaporated under reduced pressure at 20. Theresidue was dissolved in 300 ml. of absolute ether, the solutionfiltered and treated with stirring with 50 ml. of 2-M sodium 2-ethylcaproate solution in ethyl acetate. The [(R)-l-(2-furoyloxy)-3-methylbutyl]penicillin sodium which precipitatedwasfiltered off by suction, washed with absolute ether and low-boilingpetroleum ether and, after drying, recrystallized from water-isopropanolto yield a product of melting point l82l83 (with decomposition); [01],;22l.5 (c 2.0 in water).

EXAMPLE 2 [(R)-1-(isonicotinoyloxy)-3 -methylbutyl] penicillin 1 111 L(R)-2-(isonicotinoyloxy)-isocaproic acid, melting point l38l39; [01],,22.3 (c= 3 in ethanol), was prepared via its benzyl ester in a manneranalogous to that described for the preparation of the starting materialin Example 1.

A mixture of 23.7 g. of (R)-2-(isonicotinoyloxy)- isocaproic acid thusformed, 80 ml. of absolute benzene and 36 ml. of thionyl chloride waswarmed for 2 hours, evaporated and thereafter evaporated three timesunder reduced pressure at 45 with 30 ml. portions of absolute benzeneand dried. There was obtained 25.6 g. of(R)-a-(isonicotinoyloxy)-isocaproic acid chloride hydrochloride. Thiswas dissolved in 80 ml. of chloroform and added dropwise at 0 withstirring to a solution of 21.6 g. of 6-aminopenicillanic acid in amixture of 150 ml. of chloroform and 42 ml. of triethyl'amine. Thereaction mixture was kept for 20 hours at 0 and then evaporated underreduced pressure at 20. The residue was dissolved in 200 ml. ofice-water and extracted twice with 70 ml. portions of ethyl acetate. ThepH of the aqueous phase was adjusted to pH 2.5 at 0 with citric acid andextracted three times with 100 ml. portions of ethyl acetate. The ethylacetate solutions were collected and washed three times with 30 ml.portions of ice-cold percent sodium chloride solution, dried withmagnesium sulphate and evaporated under reduced pressure at 20. Theresidue was dissolved in 100 ml. of ethyl acetate and the solutiontreated with stirring with 50 ml. of 2-M sodium-2- ethylcaproatesolution in ethyl acetate and with 200 ml. of absolute ether. The[(R)-l-(isonicotinoyloxy)-3- methylbutyl]penicillin sodium whichprecipitated was filtered off by suction, washed with absolute ether andlow-boiling petroleum ether and, after drying, recrystallized fromwater/isopropanol to yield a product of melting point l97-l98 (withdecomposition); [01],, 227 (c 1.0 in water).

EXAMPLE 3 (R )-3-methyll S )pyroglutamoyloxybutyllpenicillin sodium Atotal of 14.2 g. of (S)-pyroglutamic acid were suspended in 60 ml. ofdimethylformamide and brought into solution with 15.4 ml. oftriethylamine. There was then added at 60 with stirring over 20 minutes52 ml. of a 5.2 molar solution of phosgene in toluene and, after afurther 5 minutes, with strong stirring, a solution of 22.2 g. ofbenzyl-(R)-2-hydroxyisocaproate in 80 ml. of pyridine, which has beenpreviously cooled to from about -40 to 50. The mixture was thenmaintained for 16 hours at from 2 and evaporated under reduced pressurewith a receiver cooled with dry-ice. The residue was taken up in etherand washed three times each with l-N hydrochloric acid, water, 10percent potassium bicarbonate and water, dried over sodium sulphate andevaporated under reduced pressure. The residue which containedbenzyl-(R)-2-[(S)- pyroglutamoyloxyl-isocaproate was hydrogenated inglacial acetic acid/water (:5) with 5 percent palladiisocaproic acidformed above and 6.0 ml. of triethylam-- ine in rnl. of absolutechloroform at 10 chloroform was treated with 5.2 gf of pivaloyl chlorideand stirred for 20 minutes at 10. The mixture was then cooled to 40, the6-aminopenicillanic acid solution added and the mixture subsequentlymaintained for 16 hours at 0. The solution was then evaporated underreduced pressure at a bath temperature of 20, taken up in water andextracted twice with ethyl acetate. After washing the ethyl acetate withwater and saturated sodium chloride solution and drying it over sodiumsulphate, it was concentrated in vacuum at a bath temperature of 20 to80 ml. and stirred into 800 ml. of petroleum ether. -After decantation,this procedure was repeated, chloroform being used in place of ethylacetate. The decantation residue was taken up in 100 ml. of acetone andtreated with 20 ml. of 2-M sodium-2- ethylcaproate in ethyl acetate,precipitated with petroleum ether-and decanted.- From methanol/isopropylether there crystallized(R)-3-methyl-1-[(S)-pyroglutamoyloxybutyllpenicillin sodium of meltingpoint 180 (with decomposition); [04],, 187.0 (c 1.0 in water).

EXAMPLE 4 sodium of melting point 205-206. (with decomposition); [01],,189 (0 l in water).

EXAMPLE 5 [[(R)-1-(2,6-dimethoxyisonicotinyl)oxy]-3- vmethylbutyl]penicillin sodium In a manner analogous to that described inExample 1, (R)-2-(2,6-dimethoxyisonicotinoyloxy)-isocaproic acid; mp79-81 [a],, 12.2 (c= 2 in ether) was prepared via the correspondingbenzyl ester. Using this compound as a starting material [[(R)-l-(2,6-dimethoxyisonicotinyl)oxy]-3-methylbutyl] penicillin sodium; mp (withdecomposition); [01],,

157 (c 2 in water) was prepared in accordance with the method of Example1.

EXAMPLE 6 l( R)-3-methyl- 1 -[(5-methyl-2-furoyl)oxy]butyl]- penicillinsodium In a manner analogous to that described in Example 1,(R)-2-(5-methyl-2-furoyloxy)-isocaproic acid was prepared via thecorresponding benzyl ester. Using this compound as a starting material[(R)-3-methy1-1-[(5- methyl-Z-furoyl)oxylbutyllpenicillin sodium; mp 204(with decomposition); [01] 211.3 (c l in water) was prepared inaccordance with the method of Example 1.

EXAMPLE 7 [(R)-1-[2-benzofury1oxy]-3-methylbutyllpenicillin sodium In amanner analogous to that described in Example 1,(R)-2-(2-benzofuroyloxy)-isocaproic acid was prepared via thecorresponding benzyl ester. Using this compound as a starting material[(R)-l-[2- benzofuroyloxy]-3-methylbutyl]penicillin sodium; mp 197;[01],, 183.3 (c 1 in water) was prepared in accordance with the methodof Example 1.

EXAMPLE 8 (R 1 3-methyl-5-isoxazolyl )-carbonyloxy]-3-methylbuty11penicillin sodium In a manner analogous to that described inExample 1, (R)-2-( 3-methyl-5isoxazolyl-carbonyloxy)- isocaproic acid;mp. 5962; [04],, 13 (c 2 in ethanol) was prepared via the correspondingbenzyl ester. Using this compound as a starting material [(R)-1-[(3=methyl-5-isoxazolyl)-carbonyloxy]-3- methylbutyl]penici1lin sodiummp. 185 (with decomposition), [04],, 214.3 (c 2 in water) was preparedin accordance with the method of Example 1.

EXAMPLE 9 EXAMPLE [(S)-1(2-furoyloxy)-3-methylbutyl]penicillin sodium Ina manner analogous to that described in Example 1,(S)-2-(2-furoyloxy)-isocaproic acid; [01],, 7 (0 4 in ethanol) wasprepared via the corresponding benzyl ester. Using this compound as astarting material [(S)-1-(2-furoyloxy)-3-methylbutyllpenicillin sodium;mp 150 (with decomposition) [01],, +216 (c 2 in water) was prepared inaccordance with the method of Example 1.

EXAMPLE 1 l [(Rl-3-methyll 1 ,2 ,3 ,6-tetrahydro-2 ,6-dioxo-4-pyrimidinyl)carbony1]oxy}butyl]penicillin sodium E AM E.

[(R)-3-methyl-1-{[(1methylimidazo1-4-yl)carbonyl]- mkit llrsn In amanner analogous to that described in Example 1 (R)-2-(lmethyl-4imidazolylcarbonyloxy)- isocaproic acid was prepared via thecorresponding benzyl ester. Using this compound as a starting material[(R)-3-methy1-l-{[(1methylimidazo1-4-yl)carbonyl]- oxy}butyl]penicillin; [a]D 182.8 (c= 1 in ethamlala [(R)- l-[(4-isoquino1y1carbonyl)oxy]-3- methylbutyl]penicillin sodium In amanner analogous to that described in Example 1,(R)-2-(4-isoquinolylcarbonyloxy)-isocaproic acid was prepared via thecorresponding benzyl ester. Using this compound as a starting material[(R)-1-[(4- isoquinolylcarbonyl)oxy]-3-methyl-butyl]penicillin sodium;mp 136; [a],, =+l92.7 (c= 1 in ethanol) was prepared in accordance withthe method of Example 1.

. EXAMP 14 [(R)-3-methyl- 1 1,2,3-thiadiazol-4-yl y]butyl]penicillinsodium A total of 13.0 g. of 1,2,3thiadiazol-4-carboxylic acid wassuspended in m1. of pyridine and treated dropwise at 2535 over a periodof 20 minutes with 12.8 ml. of benzene-sulphonyl chloride. The mixturewas stirred at room temperature for an additional 30 minutes to yield aclear solution. 17.9 G. of tert. butyl- (R)-a-hydroxyisovalerate werethen added over a period of 20 minutes with further stirring, thetemperature rising to ca 40. After stirring for two hours at 60, themixture was evaporated under reduced pressure, suspended in 200 ml. ofethyl acetate and filtered off. The precipitate was washed twice withethyl acetate and the combined filtrates were washed three times rapidlywith ice-cold dilute hydrochloric acid, once carbonyl)oxwith ice-waterand three times with 10 percent potasfied to Congo red and extractedthree times with ethyl' acetate. After washing-drying and evaporation ofthe solvent, there remained 19 g of a crystallizing oil.Recrystallization from isopropanol yielded 12 g. of (R)'2- 1,2,3-thiadiazol-4-yl-carbonyloxy)-isocaproic acid; melting point l04105;[01],, +20.0 (c 1 in methanol).

In a manner analogous to that described in Example 1, utilizing the(R)-2-(1,2,3thiadiazol-4-yl-car bonyloxy)-isocaproic acid thus formedthere was ob-, tained [(R)-3-methy1- 1 l ,2,3-thiadiazol-4-y1-carbonyl)oxy]buty1]penicillin sodium; mp 210 (with decomposition); [111+240.2 (c l in water).

r [(R)-3-methyl 1-{[(tetrahydropyran-4-yl)carbonyl} Ioxy}butyl]penicillin sodium(R)-2-(tetrahydropyran-4-ylcarbonyloxy)-isocapr&c

EXAMPLE 16 l' l yl-3-methylbutyl]penicillin sodium A total of 19.2 g. of1,5-dimethy1pyrazole-3- carboxylic. acid was heated at reflux for20-minutes with 80 ml. of thionyl chloride after which the excessthionyl chloride was removed under reduced pressure. The mixture wasevaporated two additional times under reduced pressure with toluene,then taken up in 100 ml. of toluene and added dropwise at 0 withstirring to 22.4 g; of tert. butyl-(R)-a-hydroxyisocaproate in 80 m1. ofpyridine. After stirring for .two hours at room temperature, the mixturewas evaporated under reduced pressure, taken up in ether and washedthree times each with water and a percent aqueous solution of potassiumbicarbonate. After drying and evaporating off the solvent, thereremained 25.5 g. of a residue of melting point 69-7l which crystallizedunder petroleum ether. This residue, which contained tert. butyl-(R)-2-(1,4-dimethylpyrazol-3-yl-carbonyloxy)- isocaproate, was left to stand atroom temperature for 30 minutes with 50 m]. of trichloroacetic acid and,after evaporation in vacuum, was dissolved in ether and exhaustivelyextracted with 10 percent potassium bi-' carbonate. After acidificationof the bicarbonate extracts to Congo red, it was extracted with etherandthe ether evaporated under reduced pressure after washing and drying.The residue which remained was recrystallized from ethyl acetate toyield 16 g. of (R)-2-(1,5- dimethy1pyrazol-3-ylcarbonyloxy)-isocaproicacid; mp 155-l6l [01],, +l3.l (c 1.0 in methanol).

In a manner analogous to that described in Example 1, utilizing the(R)-2-( l,5-dimethyl-3-pyrazolylcarbonyloxy) -isocaproic acid formedabove there was ob- .tainsdiLBJ-i-fltlsl methy a xaaqlfiv carbonynoxy-3-methylbutyl]penicillin sodium; mp

205 (with decomposition); [01],,

+196.7 (c 1 in water).

EXAMPLE l7 amide was brought into solution with 11.9 ml. oftriethylamine. It was then treated slowly at 60 with strongstirring with38.1 ml. of a 2.86 molar solution of phosgene in toluene and then asolution of 14.6 g. of tert. butyl-(R)-2-hydroxyisocaproate in 50 ml. ofpyridine which has been previously cooled to ca 50, was added in oneportion. After the mixture had reached room temperature, it wasevaporated under reduced pressure and the residue taken up in ether andwashed three times each with water and a 10 percent aqueous potassiumbicarbonate solution, dried and once more evaporated under reducedpressure. There remained 26 g. of a crystalline mass which containedtert. butyl- (R )-2-( 2-acetamido-4-thiazolecarbonyloxy isocaproate.This mass was allowed to stand for 30 minutes at room temperature with100 ml. of trifluoroacetic acid. After removal of the solvent underreduced pressure, the residue was taken up in ether and exhaustivelyextracted with 10 percent potassium bicarbonate solution. Afteracidification of the aqueous solution to pH 3, it was extracted threetimes with ethyl acetate E and the extract, after washing with water anddrying over sodium sulphate, was evaporated under reduced pressure.(R)-2-(2-acetamido-4-thiazolecarbonyloxy)- isocaproic acid remained as anon-crystalliz'ing resin.

In a manner analogous to that described in Example 3, utilizing as astarting material (R)-2-(2-acetamido-4-thiazolyl-carbonyloxy)-isocaproic acid there was obtained[(R)1-{2-acetamido-4-thiazolyl)- carbony1]oxy -3-methylbutyl] penicillinsodium; mp 220 (withdecomposition); [a],, =+l51.5 (c= 1 in 5 water).

v EXAMPL In a manner analogous to that described in Example 1, utilizingas a starting material (R)-2-[(RS)- tetrahydro-2-furoyloxy]-isocaproicacid there was obtained (R )-3-rnethyll RS)-tetrahydro-2-furoy1oxy]butyl]penicillin sodium; mp -185 (withdecomposition); [01] +200 (c 1 in water).

EX LE. 1?, o

analogous to that described for the preparation of the starting materialin Example 35.

In a manner analogous to that described in Example I, utilizing as astarting material (RS)-2-(2-furoyloxy)- valeric acid there was obtained(RS)-1-(2-furoyloxy)- butyl penicillin sodium; mp l65-l 70 (withdecomposition); [041 +209 (c l in water).

EXAMPLE 20 (RS l l ,6-dihydro-fi-oxonicotinoyl )-oxy]-3-methylbutyl]penicillin sodium (RS )-2-(1,6-dihydro-6-oxonicotinoyloxy)-is0caproic acid, melting point 167-l 70,was prepared via its benzyl ester in a manner analogous to thatdescribed for the preparation of the starting material in Example 35.

In a manner analogous to that described in Example 1, utilizing as astarting material (RS)-2-(l,6-dihydro- 6-oxonicotinoyloxy)-isocaproicacid there was obtained [(RS)- 1-[( 1,6-dihydro-6-oxonicotinoyl)-oxy]-3-methylbutyl]penicillin sodium; mp 200 (with decomposition); [01],, =+l9l(c 1 in water).

EXAMPLE 21 (R )-3-methyll (pyrazinylcarbonyl )oxy]butyl]- penicillinpotassium (R)-2-(pyrazinylcarbonyloxy)-isocaproic acid was prepared viaits tert. butyl ester in a manner analogous to that described for thepreparation of the starting material in Example 17.

In a manner analogous to that described in Example 3, utilizing thethus-formed (R)-2-(pyrazinylcarbonyloxy)-isocaproic acid, there wasobtained [(R)-3- methyl-l-[(pyrazinylcarbonyl)oxy]butyl]penicillinpotassium; mp 150 (with decomposition); [01],, =+186.5 (c l in water).

EXAMPLE 22 [(R )-3-methyll l-oxidonicotinoyl)oxy]butyl]- penicillinsodium A total of 17.8 g of nicotinoyl chloride hydrochloride wasdissolved in 150 ml of pyridine and 50 ml of dimethylformamide and thesolution treated slowly with stirring at a temperature not over 15 with22.2 g of be nzyl-(R)-a-hydroxy-isovalerate (prepared from(R)-2-hydroxy-isovaleric acid and benzyl chloride in a manner analogousto that describedfor the preparation of the corresponding compound inExample 1). After stirring for 2 hours at room temperature, the mixturewas evaporated under reduced pressure. The residue was taken up inether, washed three times with water and extracted six times withice-cold 3-N hydrochloric acid. The hydrochloride phases wereimmediately allowed to run into saturated sodium bicarbonate solutionand the base which was thus released was extracted three times withether. After washing and drying, it was evaporated under reducedpressure and there were obtained 27 g of a resin which containedbenzyl-(R)-2-(nicotinoyloxy)-isocaproate. The resin was thenhydrogenated in 200 ml. of ethanol with 2 g. of percentpalladium-on-charcoal until 2 equivalents of hydrogen had been taken up.After filtration and evaporation, the residue was taken up in percentpotassium bicarbonate, washed twice with ether and adjusted to pH 3withcitric acid. After extraction with ether, washing, drying andevaporation of the extract, there was obtained a crystallizing oil.Recrystallization from ethyl acetate/petroleum ether yielded 14 g of(R)- 2-(nicotinoyloxy)-isocaproic acid; mp l0l103; [11],, +18.8 (c 1.0in methanol).

The N-oxide of the above acid was obtained by dissolving 26.4 g. of itin ml. of glacial acetic acid by treating for three hours at 7080 with11 ml. of 30 percent hydrogen peroxide. After the addition of anadditional 8 ml. of 30 percent hydrogen peroxide, the mixture was leftovernight at the same temperature. The mixture was then cautiouslyevaporated under reduced pressure and evaporated off twice with 50 ml.portions of water, care being taken to ensure that the mixture is neverevaporated to dryness. This residue was taken up in chloroform, washedfour times with water, dried and evaporated under reduced pressure.Recrystallization from ethyl acetate yielded 19 g of(R)-2-nicotinoyloxy-isocaproic acid N-oxide; mp l32-l34; [011 =+20.8 (c1.0 in methanol).

In a manner analogous to that described in Example 1, utilizing thethus-formed (R)-2-(nicotinoy1oxy)- isocaproic acid N-oxide there isobtained [(R)-3- methyl- 1 1-oxidonicotinoyl)oxy]butyl lpenicillinsoium; mp 175 (with decomposition); [01],, =+l 68.3 (c l in water).

EXAMPLE 23 [(R)-l-[(4-chloropicolinoyl)oxy]-3- methylbutyl]penicillinsodium (R)-2-(4-chloropicolinoyloxy)-isocaproic acid (melting pointl20-122) was prepared via its tert. butyl ester in a manner analogous tothat described for the preparation of the starting material in Example17.

In a manner analogous to that described in Example 3, utilizing theabove (R)-2-(4-chloropicolinoyloxy)- isocaproic acid there was obtained[(R)-l-[(4- chloropicolinoyl)oxy]-3-methyl-butyllpenicillin sodium;melting point (with decomposition); [01],, ==+146.7 (c 1 in water).

EXAMPLE 24 [(R)-l-[(2,6-dichloroisonicotinoyl)oxy]-3-methylbutyl]penicillin sodium(R)-2-(2,6-dichloroisonicotinoyloxy)-isocaproic acid melting point 798l(with decomposition) was prepared via its tert. butyl ester in a manneranalogous to that described for the preparation of the starting materialin Example 16.

In a manner analogous to that described in Example 1 utilizing the above(R)-2-( 2,6- dichloroisonicotinoyloxy)-isocaproic acid there wasobtained [(R)-l-[(2,6-dichloroisonicotinoyl)oxy]-3-methylbutyl]penicillin sodium; mp. from 162 (with decomposition); [ad+164.6 (c 2 in water).

EXAMPLE 25 [(R)-1-[( i-oxazolylcarbonyl)oxyl-S- methylbutyl]penicillinsodium (R)-2-(4-oxazolylcarbonyloxy)-isocaproic acid was prepared viaits benzyl ester in a manner analogous to that described for thepreparation of the starting material in Example 1.

In a manner analogous to that described in Example 1, utilizing as astarting material (R)-2-(4-oxazolylcarbonyloxy)-isocaproic acid therewas obtained [(R)-1- [(4-oxazolylcarbonyl)oxy]-3-methylbutyl]penicillin15 sodium; mp 173 (with decomposition); =+l50.8 (c l in ethanol).

EXAMPLE 26 (R )-3-methyll 2-methylisonicotinoyl )oxy butyllpenicillinsodium (R)-2-( 2-methylisonicotinoyloxy)-isocaproic acid was preparedvia its benzyl ester in a manner analogous to that described for thepreparation of the starting material in Example 22.

In a manner analogous to that described in Example 1 utilizing thethus-formed (R)-2-( 2- methylisonicotinoyloxy)-isocaproic acid there wasobtained [(R)-3-methyll (2-methyl-isonicotinoyl )oxy]- butyllpenicillinsodium; mp l95200 (with decomposition); [011 =+l88 (c l in water).

EXAMPLE 27 (R l 3-isoxazolylcarbonyl )oxy]-3- methylbutyllpenicillinsodium (R)-2-(3-isoxazolylcarbonyloxy)-isocaproic acid was prepared viaits benzyl ester in a manner analogous to that described for thepreparation of the starting material in Example 1.

In a manner analogous to that described in Example 1, utilizing theabove (R)-2-(3-isoxazolylcarbonyloxy)- isocaproic acid there .wasobtained [(R)-l-[(3- isoxazolylcarbonyl)oxy]-3-methylbutyl1penicillinsodium; mp 188 (with decomposition); [(21 =+209.6 (c l in ethanol).

EXAMPLE 28 [(R)- l 3-indolylcarbonyl)oxy1-3- methylbutyl]penicillinsodium The (R)-2-(3-indolylcarbonyloxy)-isocaproic acid was prepared viaits benzyl ester in a manner analogous to that described for thepreparation of the starting material in Example 1.

In a manner analogous of that described in Example 1, utilizing as astarting material (R)-2-(3- isoxazolylcarbonyloxy)-isocaproic acid therewas obtained [(R)-l-[(3-isoxazolylcarbonyl)-oxy]-3-methylbutyl1penicillin sodium; mp 188 (with decomposition); .[crl=+209.6 (c l in ethanol).

EXAMPLE 29 EXAMPLE 3O (RS l -[(2,G-dimethylisonicotinoyl )oxy]-3-methylbutyllpenicillin sodium(RS)-2-(2,6-dimethylisonicotinoyloxy)-isocaproic acid (mp. 9596) wasprepared via its benzyl ester in a manner analogous to that describedfor the preparation of the starting material in Example 35. Theresulting compound was treated with thionyl chloride to yield(RS)-2-(2,6-dimethylisonicotinoyloxy)- isocaproic acid hydrochloride.

In a manner analogous to that described in Example 2, utilizing theabove (RS)-2-(2,6-dimethylisonicotinoyloxy)-isocaproic acidhydrochloride there was obtained [(RS l 2,6-dimethylisonicotinoyl)oxy]-3-methylbutyl]penicillin sodium; [01],, =+l59(c 2 in water).

EXAMPLE 3 l [(R)-1-cinchoninoyloxy)-3-methylbutyl]penicillin sodium(R)-2-(cinchoninoyloxy)-isocaproic acid was prepared via its benzylester in a manner analogous to that described for the preparation of thestarting material in Example 1.

In a manner analogous to that described in Example 1, utilizing thethus-formed (R)-2-(cinchoninoyloxy)- isocaproic acid there was obtained[(R)-lcinchoninoyloxy)-3-methylbutyl]penicillin sodium; mp 143 (withdecomposition); [01],, ==+208.7 (c l in ethanol).

EXAMPLE 32 [(R)-l-[(7-chlorocinchoninoyl)oxy]-3- methylbutyHpenicillinsodium (R)-2-(7-chlorocinchoninoyloxy)-isocaproic acid was prepared viaits benzyl ester in a manner analogous to that described for thepreparation of the starting material in Example 1.

In a manner analogous to that described in Example 1, utilizing as astarting material (R)-2-(7-chlorocinchoninoyloxy)-isocaproic acid therewas obtained [(R- )-l-[(7-chlorocinchoninoyl)oxy]-3-methylbutyl1penicillin sodium; mp (with decomposition); [(11 =+l96.4 (cl in ethanol).

EXAMPLE 33 [(R)-l-[(2-chloronicotinoyl)oxy]-3- methylbutyl lpenicillinpotassium (R)-2-(2-chloronicotinoyloxy)-isocaproic acid; mp

pared via tert. butyl ester in a manner analogous to that described forthe preparation of the starting material in Example 16.

In a manner analogous to that described in Example 1, utilizing theabove (R)-2-(2-chloronicotinoyloxy)- isocaproic acid there was obtained[(R)-l-[(2- chloronicotinoyl)oxy]-3-methylbutyl]penicillin potassium; mp120 (with decomposition); [01],, =+167.3 (c l in water).

EXAMPLE 34 [(R)-3-methyll -(quinaldoyloxy)-butyl]penicillin sodium v(R)-2-(quinaldoyloxy)-isocaproic acid was prepared via its benzyl esterin a manner analogous to that described for the preparation of thestarting material in Example 22.

In a manner analogous to that described in Example I, utilizing thethus-formed (R)-2-(quinaldoyloxy)- isocaproic acid there was obtained[(R)-3-methyl-l- (quinaldoyloxy)-butyl]penicillin sodium; mp

(with decomposition); [01],, =+l l9.3 (c 1 in ethanol).

EXAMPLE 35 [(RS)-1-(isonicotinoyloxy)-3-methylbutyl]penicillin sodium Atotal of 29.5 g of benzyl-(RS)-a-bromoisocaproate was added dropwise at60 with stirring over a period of 15 minutes to a solution of 12.8 g ofisonicotinic acid in a mixture of 60 ml. of dimethylformamide and 14.8ml of triethylamine. The reaction mixture was stirred for 5 hours at 90.The triethylamine hydrobromide was then filtered off by suction and thefiltrate evaporated under reduced pressure at 60. The residue wasdissolved in 100 ml of ethyl acetate and filtered and the filtratewashed three times with 15 ml portions of l-N potassium bicarbonatesolution and twice with 20 ml portions of water. The ethyl acetatesolution was dried with magnesium sulphate and evaporated under reducedpressure at 45. Benzyl-(RS)-2- (isonicotinoyloxy)-isocaproate wasobtained as an oil.

For purification, the ester formed above was dissolved in 10 ml of ethylacetate and the resulting solution mixed with a solution of 19 g ofp-toluenesulphonic acid in 35 ml. of ethyl acetate and crystallized for2 hours at The resulting benzyl-(RS)-2- (isonicotinoyloxy)-isocaproatep-toluene-sulphonate was filtered off by suction, washed with 100 ml ofether and dried under reduced pressure at 60 to give a compound ofmelting point 136. The p-toluenesulphonate was dissolved in 30 ml ofwater, the solution adjusted to pH 9 with potassium carbonate andextracted twice with 50 ml portions of ethyl acetate. The ethyl acetatesolution was washed twice with 10 ml portions of water, dried withmagnesium sulphate and evaporated under reduced pressure at 40.Crystallization of the resulting oil from low-boiling petroleum ethergave benzyl-( RS 2-(isonicotinoyloxy)-isocaproate; mp 4950.

8.2 g of benzyl-(RS)-2-(isonicotinoyloxy)- isocaproate were hydrogenatedin 50 ml of alcohol after the addition of 800 mg. ofpalladium-on-charcoal percent) until the theoretical amount of hydrogenhad been taken up. The catalyst was then filtered off and the filtrateevaporated under reduced pressure at 45. The resulting oil was dissolvedin excess sodium bicarbonate solution and extracted twice with 20 mlportions of ether and the bicarbonate solution adjusted to pH 2.5 with3-N hydrochloric acid. The acidic solution was extracted twice with 70ml portions of ethyl acetate. After being washed twice with 20 mlportions of 5 percent sodium chloride solution, the ethyl acetatesolution was dried with magnesium sulphate and evaporated under reducedpressure at 45. The resulting oil was crystallized from ether/petroleumether to yield (RS)-2-(isonicotinoyloxy)-isocaproic acid; mp 98-100.

In a manner analogous to that described in Example l, utilizing as astarting material (RS)-2- (isonicotinoyloxy)-isocaproic acid there wasobtained (RS 1 isonicotinoyloxy )-3-methylbutyl]penicillin sodium;[01],, +197.5 (c 2 in water).

EXAMPLE 36 [(RS l -(isonicotinoyloxy )butyl]penicillin sodium The(RS)-2-(isonicotinoyloxy)-valeric acid, melting point l52-153 wasprepared via its benzyl ester in a manner analogous to that describedfor the preparation of the starting material in Example 35.

In a manner analogous to that described in Example 2, utilizing as astarting material (RS)-2- (isonicotinoyloxy)-valeric acid there wasobtained [(R- S l isonicotinoyloxy)-butyl ]penicillin sodium; [or] =+222(c 2 in water). I

EXAMPLE 37 [(R)-l-(nicotinoyloxy)-3-methylbutyl]penicillin potassium(R)-2-(nicotinoyloxy)-isocaproic acid was prepared via its benzyl esterin a manner analogous to that described for the preparation of thestarting material in Example 22.

In a manner analogous to that described in Example 1, utilizing as astarting material (R)-2-(nicotinoyloxy)- isocaproic acid there wasobtained [(R)-l- (nicotinoyloxy )-3-methylbutyl ]penicillin potassium;mp (with decomposition); [011 +210.4 (c l in water).

EXAMPLE 38 [(R)-3-methyl-l-(2-thenoyloxy)butyl]penicillin dium The(R)-2-(2-thenoyloxy)-is0caproic acid [01],, =+l3.7 (c 2 in ethanol) wasprepared via its tert. butyl ester in a manner analogous to thatdescribed for the preparation of the starting material in Example 16.

In a manner analogous to that described in Example 1, utilizing theabove (R)-2-(2-thenoyloxy)-isocaproic acid there was obtained[(R)-3-methyl-1-(2-thenoyloxy)butyl]penicillin sodium; [011 =+l03 (c lin water).

EXAMPLE 39 [3-methyl-1-[(pyrrol-2 ylcarbonyl)- oxy]butyl]penicillinsodium 2-(2-pyrrolylcarbonyloxy)-isocaproic acid was prepared via itsbenzyl ester in a manner analogous to that described for the preparationof the starting material in Example 35.

In a manner analogous to that described in Example 3, utilizing theabove 2-(2-pyrrolylcarbonyloxy)- isocaproic acid there was obtained[3-methyl-l- [(pyrrol-2-ylcarbonyl)oxy]butyl]penicillin sodium as adiastereomeric mixture; mp 208 (with decomposition); [01],, =+l87.5 (c lin ethanol).

EXAMPLE 4O EXAMPLE 41 [(R)- l (2,4-dimethyl--pyrimidinylcarbonyl )oxy]-3- methylbutyl]penicillin sodium(R)-2-(2,4-dimethyl-S-pyrimidinylcarbonyloxy)- isocaproic acid, an oilysubstance, was prepared via its benzyl ester in a manner analogous tothat described for the preparation of the starting material in ExampleIn a manner analogous to that described in Example 3, utilizing as astarting material (R)-2-(2,4-dimethyl-5-pyrimidinylcarbonyloxy)-isocaproic acid there was obtained[(R)-l-[(2,4-dimethyl-5-pyrimidinylcarbonyl)oxy]-3-methylbutyl]penicillin sodium, mp 185 (withdecomposition); [01],, =+225 (c l in water).

EXAMPLE 42 [(R)-l-[(S-pyrimidinylcarbonyl)oxy]-3- methylbutyl]penicillinsodium (R)-2-(5-pyrimidinylcarbonyloxy)-isocaproic acid, an oilysubstance, was prepared via its benzyl ester in a manner analogous tothat described for the preparation of the starting material in Example1.

In a manner analogous to that described in Example 3, utilizing thethus-formed (R)-2-(5-pyrimidinylcarbonyloxy)-isocaproic acid there wasobtained [(R)-1- [(5-pyrimidinylcarbonyl)oxy]-3-methylbutyl]penicillinsodium; mp 205 (with decomposition); [011 =+237 (c lin ethanol).

EXAMPLE 43 EXAMPLE 44 [(R)- l-(5-methoxymethyl-2-furoyloxy)-3-methylbutyl]penicillin sodium(R)-2-(5-methoxymethyl-2-furoyloxy)-isocaproic acid (melting point 7374)was prepared via its benzyl ester in a manner analogous to thatdescribed for the preparation of the starting material in Example 1.

In a manner analogous to that described in Example 1, utilizing as astarting material (R)-2-(5- methoxymethyl-2-furoyloxy)-isocaproic acidthere was obtained (R l 5methoxymethyl'2-furoyloxy )-3- position); [a],,=+203 (c l in water).

EXAMPLE 45 [(R )-3-methyll -[(S)-5-oxotetrahydro-2-furoyloxy]-butyllpenicillin sodium (R )-2-[ S )5-oxotetrahydro-2-furoyloxyl-isocaproic methylbutyl]penicillin sodium; mp 173 (with decomacid; mpll5-l 16; [a],, =+23.4 (c=0.5 in dioxan) was prepared via its benzylester in a manner analogous to that described for the preparation of thestarting material in Example 22.

In a manner analogous to that described in Example 1, utilizing as astarting material (R)-2-[(S)-5- oxotetrahydro-Z-furoyloxy]-isocaproicacid there was obtained [(R)-3-methyll (S )-5-oxotetrahydro-2-furoyloxy]butyl]penicillin sodium; mp 216 (with decomposition); [011=+235 (c l in water).

EXAMPLE 46 [(R)-3-methyll R)-5-oxotetrahydro-2-furoyloxy]-butyl]penicillin sodium(R)-2-[(R)-5-oxotetrahydro-2-furoyloxy]-isocaproic acid, an oilysubstance, prepared'via its benzyl ester in a manner analogous to thatdescribed for the preparation of the starting material in Example 22.

In-a manner analogous to that described in Example 1, utilizing thethus-formed (R)-2-[(R )-5- oxotetrahydro-2-furoyloxy]-isocaproic acidthere was obtained [(R)-3-methyl- 1 (R)-5-oxotetrahydro-2-furoyloxy]butyl]penicil1in sodium; mp 215 (with decomposition; [a] =+l96(c l in water).

Example 47 The following composition was prepared as follows and filledinto gelatin capsules.

Ingredient [(R l 2-furoyloxy)3-methylbutyl] Amount per Capsule enicillinsodium 526 mg. UVl SKOL K (l) 3 mg. Mannitol 20 mg. Talc 19 mg.Magnesium stearate 2 m Total 6U!) mg.

l Adpolyvinfyl pyrrolidorle E'oduct manufactured by Badische Anilin u.Sodafabrik. Lu wlgshu en am Rhem. ermun Federal Republic.

The penicillin was homogeneously blended with the LUVISKOL and mannitoland compressed into slugs. The slugs were then passed through a suitablesieving machine and, after blendin with the tack and magnesium stearate,filled into suitable gelatin capsules.

EXAMPLE 48 Reconstitutable injectable preparations were prepared bylyophilizing and hermetically sealing ampoules each containing 2 ml. ofa sterile solution coni taining 263 mg. of [(R)-l-(2-furoyloxy)-3-methylbutyl]penicillin sodium, 1.1 mg. of methyl-phydroxybenzoatehydroxybenzoate.

We claim:

1. A compound of the formula OOH wherein A is selected from the groupconsisting of fu- I ryl', tetrahydrofuryl andthien l, and T is selectedfrom the group; consisting'of C alke'ny-l, cyclopropylmethyl,cFclIobut-ylmethyl and cyclopentyl and pharmaceutical forms thereof.

25A compound selected from the group consisting of(R)-l-(2-furoyloxy)-3-methylbutyl-penicillin and harmaceuticallyacceptable salts and hydrated orms thereof.

and 0.135 mg. of propyl-p-.

y acceptable salts and hydrated

1. A COMPOUND OF THE FORMULA
 2. A compound selected from the groupconsisting of (R)-1-(2-furoyloxy)-3-methylbutyl-penicillin andpharmaceutically acceptable salts and hydrated forms thereof.